Dialysis adequacy is the topic that has got and gets more attention when one thinks about patient outcome. In order to estimate dialysis adequacy one needs a parameter establishing a relation between dialysis dosage and patient outcome. The most accepted parameter to estimate the quantity of dialysis delivered or dosage is the Kt/V, where K is the effective clearance for urea, t is the treatment time and V is the urea distribution volume which matches the total body water.
The NCDS (National Cooperative Dialysis Study) and the HEMO study found, after analyzing a large patient group, that morbidity and mortality in end stage renal disease (ESRD) was strongly correlated with the Kt/V value or dialysis dose. Data obtained from these studies resulted in guidelines regarding hemodialysis treatments, which demand a minimum dose of Kt/V=1.2 for non-diabetic patients and 1.4 for diabetics (DOQI guidelines). It is worthy to point out that a morbidity decrease not only improves the patient well-being, but also reduces significantly the medical costs as the patient requires less care.
The need of a reliable and cost effective method to monitor the Kt/V and by extension control dialysis adequacy and morbidity, would therefore be easily understood to one of ordinary skill in the art from the description herein.
In the Kt/V calculation, the main problems are K and V estimation along with the multicompartment urea kinetics. V can be estimated by bioimpedance, anthropometric measurements or applying the urea kinetic model (UKM), all these methods have a certain degree of error. K can be estimated so far by measuring the urea blood concentration before and after the treatment or by monitoring inlet and outlet conductivity changes in the dialysate side.
Blood samples method is the reference one. After taking the blood samples and applying either UKM or Daugirdas formula a single pool Kt/V (spKt/V) is estimated, further, Daugirdas second generation formulas should be used to get an equilibrated Kt/V (eKt/V) which accounts for the urea rebound caused by the fact that urea kinetic's does not follow a single pool model but a multi-compartment one. This method has two main problems: it is not possible to know whether the treatment is adequate or not before it finishes, therefore it is not possible to perform any action to improve the situation; it is not an easy to apply method: sampling time is very important to get an accurate value, and the medical staff must send the samples to the lab, wait for the results and calculate Kt/V values with the help of a computer. These facts result on a monthly basis Kt/V measurements in best case, which means that in worst case scenario a patient might be under-dialyzed for one whole month.
Conductivity methods are based on the observation that sodium clearance is almost equal to urea clearance and that the relationship between dialysate conductivity and dialysate sodium concentration can be considered linear on the temperature range of interest. Therefore it is possible to get urea clearance by measuring the sodium diffusion transport through the membrane in the dialyzer.
It is important to introduce the concept of Dialysance, as it slightly differs from Clearance:
Clearance is defined as the ratio between transport rate and concentration multiplied by flow, and it is applicable when the diffusing substance is on the blood side but not on the dialysate, that is the case for urea.
Dialysance is defined as the ratio between transport rate and concentration gradient multiplied by flow, and it is applicable when the diffusing substance is in both dialyzer sides. When one applies conductivity methods to measure urea Clearance, one actually measures sodium Dialysance (see Depner T, Garred L. Solute transport mechanisms in dialysis. Hörl W, Koch K, Lindsay R, Ronco C, Winchester J F, editors. Replacement of renal function by dialysis, 5th ed. Kluwer academic publishers, 2004:73-91).
During conductivity based clearance measurements, a dialysate inlet conductivity different to the blood one is produced, which results in a net transfer of sodium either from blood to dialysate or from dialysate to blood due to the generated gradient. There are currently several methods which are applied in the industry:
In a first method a one-step conductivity profile is performed; in a second method a two-step conductivity profile is performed; and in a third method an integration of conductivity peaks is used. (see Polaschegg H D, Levin N W. Hemodialysis machines and monitoris. Hörl W, Koch K, Lindsay R, Ronco C, Winchester J F, editors. Replacement of renal function by dialysis, 5th ed. Kluwer academic publishers, 2004:414-418). The main advantages of this approach is that it is relatively easy to implement and cost effective as it only needs an extra conductivity/temperature sensor downstream the dialyzer. It offers Kt/V measurements during the treatment allowing the medical staff to react and perform some actions in case the treatment is not going as it should. However, conductivity based methods have also some limitations: they can induce some sodium load in the patient during the measurement; they are not useful to obtain other interesting parameters like nPCR or TRU. The maximum measurement frequency offered so far by the industry is about 20 minutes, which means that in worst case scenario the patient could be under-dialyzed for 20 minutes. And although there are some publications claiming it, so far, conductivity methods haven't been applied with enough reliability to hemofiltration or hemodiafiltration treatments.
Another method to estimate hemodialysis adequacy is by direct measurement of the waste products (urea) concentration in the effluent dialysate, this method assumes that the evolution of urea concentration over the time in the dialysate side is proportional to the one in the blood, therefore the slope of the line obtained after applying the natural logarithm to the registered concentration values over the time will be the same on both sides: dialysate side and blood side. And by definition such slope is K/V, which multiplied by the therapy time results in the Kt/V value.
There are two different methods available to measure online the concentration of waste products in effluent dialysate: Urea sensors and UV spectrophotometry.
The limitations of the urea sensors are well known. Recent works carried out by Fridolin I. et al (see I. Fridolin, M. Magnusson, L.-G. Lindberg. On-line monitoring of solutes in dialysate using absorption of ultraviolet radiation: Technique description. The International Journal of Artificial Organs. Vol. 25, no. 8, 2002, pp. 748-761) and Uhlin F. (see Uhlin F. Haemodialysis treatment monitored online by ultra violet absorbance. Linköping University Medical Dissertations n° 962. Department of Medicine and Care Division of Nursing Science & Department of Biomedical Engineering. 2006.) have shown that UV spectrophotometry is a reliable and cost affordable method to monitor waste products in effluent dialysate. Additionally, the European Patent EP1083948B1 describes a sensor coupled with the dialysate flow system of a dialysis machine, which is actually an UV spectrophotometer measuring UV absorbance of UV absorbing products in spent dialysate.
Using any of the online measuring methods it is possible to know the delivered Kt/V at any treatment time, but it is not possible to predict with enough accuracy how much Kt/V will be delivered to the patient at the end of the dialysis session. Such information would be of great value for the physician in order to adjust the treatment parameters and improve the dialysis efficiency.
The delivered Kt/V by unit of time it is not constant during the treatment because of the multi-compartment nature of the urea kinetic model. During the dialysis treatment we can speak about two clearances, one between the dialysate and the extra cellular compartment, and another between intra and extra cellular compartment, which is smaller than the first one. On the first stage of the dialysis treatment the extra cellular compartment is quickly cleared, further on, the concentration decrease of waste products in blood slows down because the dialyzer clearance is limited by the clearance between compartments, in other words the uptake of waste products by the extra cellular from the intra cellular compartment is smaller than the dialyzer blood clearing capabilities. From the mathematical point of view it can be noticed by the fact that the ratio K/V decreases, thus the Kt/V by unit of time also decreases as the dialysis goes on.
The shortcomings of the methods measuring the clearance by means of conductivity have been already described, besides it linearizes the Kt/V along the whole dialysis treatment and introduce a prediction error because of both the low measurement frequency and the approximation of V.
When measuring Kt/V by means of the data delivered by any sensor or measuring device, which is able to continuously measure any waste product on spent dialysate, the high measuring frequency and the wealth of data allow to make an accurate prediction of the final Kt/V value.